Improvement of Dissolution Rate of Gliclazide Through Sodium Salt

dx.doi.org/10.14227/DT210414P49

Dina El-Sabawi* and Imad I. Hamdan Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan

ABSTRACT Gliclazide is a hypoglycemic agent exhibiting to some extent inadequate and variable absorption as a consequence of poor aqueous solubility and slow dissolution rates. A sodium salt of gliclazide was prepared and investigated for solubility and dissolution properties in comparison to untreated gliclazide. The salt was formed by adding equimolar amounts of gliclazide and sodium hydroxide in an aqueous–ethanolic phase. To confirm salt formation, sodium gliclazide was fully characterized by spectroscopy, differential scanning calorimetry, and potentiometric titration. Furthermore, solubility and in vitro dissolution studies of formulated tablets were performed at pH values of 1.2, 4.5, and 6.8. Sodium gliclazide demonstrated a significant increase in solubility at pH values of 4.5 and 6.8. The most apparent increase was achieved in unbuffered distilled water with a 235-fold higher solubility. Moreover, sodium gliclazide showed an enhancement in the dissolution rate in all tested media, but most significantly at pH 4.5 and 6.8. The highest difference (60%) in dissolution rate between gliclazide and its sodium salt was obtained at pH 6.8 at 30 min. The sodium salt of gliclazide presents improved solubility and drug dissolution, therefore limiting the possibility of variable absorption and improving the onset of action with potential enhancement in its overall bioavailability. KEYWORDS: Solubility; dissolution; sodium gliclazide; antidiabetic; onset.

INTRODUCTION solubility of such drugs (15–19). Enhanced GLZ dissolution he rate of dissolution of active ingredients exhibit- was also achieved via formulation of ordered mixtures of ing poor aqueous solubility is a fundamental deter- the hydrophobic drug with water-soluble carriers of larger T minant of rate of absorption, hence oral bioavailabil- particle size such as mannitol and lactose (7). Cationic ity (1). According to the Biopharmaceutics Classification and anionic surfactant micelles have also been studied as System (BCS), the dissolution of drugs demonstrating low solubility enhancers for GLZ (5). solubility–high permeability (Class II) may be considered Oral absorption of GLZ is accelerated when the drug as the rate-limiting step through which possible in vivo is suspended in polyethylene glycol 400 and contained behavior may be anticipated in terms of onset of action in a soft gelatin capsule (20). On the other hand, float- and intensity of pharmacological effect (2, 3). It is there- ing alginate beads utilizing biodegradable polymers fore recommended to conduct the in vitro assessment of are able to maintain reduced blood glucose levels as a dissolution of Class II drugs in multiple media as an indica- consequence of improved systemic absorption of GLZ tive test of their in vivo effect (4). (21). The solubility of GLZ increased significantly with Gliclazide (GLZ) is an oral hypoglycemic sulfonylurea de- pH modification of the medium (water and phosphate rivative (Figure 1) that is commonly used for the treatment buffers at different pH values) combined with the use of of noninsulin dependent diabetes mellitus. Being a Class different cosolvents (22). II drug with low aqueous solubility (5–7), GLZ exhibits an In another study (23), the in situ micronization of GLZ unpredictable and slow absorption rate that may in turn through recrystallization in the presence of various reflect considerable intra- and intersubject variability (8). stabilizers achieved a desired morphology of crystals Various attempts aimed at improving solubility and dis- that exhibited a faster dissolution rate. In situ microniza- solution rate of GLZ have been reported. One approach tion techniques produce more thermodynamically stable involves the preparation of solid dispersions of GLZ with micron-sized particles than conventional high energy hydrophilic carriers such as polyethylene glycols through milling procedures, which was found to be advantageous applying different methodologies including fusion tech- for certain formulation aspects (6, 23). niques (9–12), cogrinding methods (13), solvent melting, These studies suggest various mechanisms through and solvent evaporation methods (14). which the solubility of GLZ is increased. These mecha- Another approach that has been investigated extensive- nisms may involve decreased aggregation of hydrophobic ly is the complexation of poorly water-soluble drugs with particles and therefore increased wettability and dispers- cyclodextrins, which was found to improve the aqueous ability, decreased particle size, limited particle surface energy variations, a change in crystal habit, and conver- *Corresponding author. sion from crystalline to amorphous state. Dissolution Technologies | NOVEMBER 2014 49 GLZ samples prepared according to the KBr disk method. IR spectra were determined between 500 and 4000 cm-1. 1H nuclear magnetic resonance (NMR) spectra were recorded for GLZ and Na–GLZ samples using a 350 MHz Bruker NMR spectrometer. Furthermore, UV characterization was conducted of GLZ and Na–GLZ solutions at 25 μg/mL. Absorption spectra were recorded in the range of 200–350 nm.

Potentiometric Titration of Na–GLZ Figure 1. Chemical structure of gliclazide. A sample of solid Na–GLZ (150 mg) was dissolved in 30 mL of distilled water and titrated potentiometrically with standardized 0.1 M HCl against 200 mg of sodium carbon- Another well-accepted approach for improving the ate. HCl was added in increments of 0.5 mL until the pH solubility and dissolution rate of low aqueous solubility became almost constant for five successive readings. The drugs is to prepare a suitable salt form of the drug (24, 25). end point was determined from the maximum point in However, to the best of our knowledge, there has been no the first derivative plot of the titration curve. salt form reported for GLZ. In this study we describe the preparation, characterization, and in vitro evaluation of a Solubility Studies sodium salt of GLZ (Na–GLZ). Solubility studies were conducted in an attempt to determine the saturation solubility of untreated GLZ and MATERIALS AND METHODS Na–GLZ in different media: pH 1.2, 4.5, and 6.8 in addition Materials to distilled water. Gradual addition of untreated GLZ or GLZ was a gift from Pharma International (Amman, Na–GLZ to glass vials containing 1 mL of each medium Jordan). Potassium dihydrogen phosphate was obtained was carried out until the solid added no longer dissolved from Sigma–Aldrich (Germany). HPLC grade acetonitrile and a precipitate was clearly present. The glass vials and ethanol were obtained from Tedia Company (Tedia were placed in a shaker water bath at 37 ± 0.1 °C for Inc., USA). Sodium hydroxide was obtained from Gainland 48 h to reach equilibrium. Subsequently, the contents Chemical Company (UK). were filtered through 0.45-µm syringe filters. A volume of 100 µL was withdrawn from the filtrate, suitably diluted, Preparation of Na–GLZ and analyzed by high performance liquid chromatogra- Nine grams of powdered GLZ were dissolved in a solu- phy (HPLC). tion composed of 700 mL ethanol and 200 mL distilled The HPLC system comprised a UV detector (Merck–Hi- water. An equimolar amount of sodium hydroxide (as tachi, model L-7400, Tokyo-Japan), a pump (Merck–Hi- 1 M solution) was added to the solution and mixed well. tachi, model L-7400, Tokyo-Japan), and an integrator Immediately a very fine precipitate appeared, and the unit (Merck–Hitachi, model D-7500, Tokyo-Japan). The mixture was left on standing for 30 min. The precipitated chromatographic conditions were based on a previous- material was filtered, left to dry for 2 h in a fume cupboard, ly published method (26). In brief, a reversed phase and then placed in a desiccator for 48 h. C18 column was employed (5 μm, 200 × 4.6 mm i.d., Thermo Scientific, USA). The mobile phase consisted Differential Scanning Calorimetry (DSC) of a mixture containing 40% acetonitrile and 60% of Untreated GLZ and Na–GLZ were subjected to differen- 25 mM phosphate buffer at pH 3.5 and was run at a flow tial scanning calorimetric analyses using a Mettler Toledo rate of 2 mL/min. The monitoring wavelength was set at calorimeter (Mettler, Toledo DSC823e, Switzerland) con- 235 nm. figured to a Mettler Star software system (Mettler, Toledo, Switzerland). Powder samples (4–5 mg) were weighed and Partition Coefficient (log P) Determination scanned in sealed 40-µL aluminium pans with pierced cov- Octanol/water partition coefficient was determined as ers. The instrument was calibrated with indium as a refer- log (coctanol/cwater) for both untreated GLZ and Na–GLZ. ence. Thermograms were recorded under dry nitrogen Untreated GLZ or Na–GLZ (20 mg) was added to glass atmosphere (80 mL/min) over a 30–350 °C temperature tubes containing 5 mL of octanol and 5 mL of distilled range and at a heating rate of 10 °C/min. water. The tightly closed tubes were placed in a shaker water bath at 37 ± 0.1 °C for 24 h. The concentrations of Spectroscopic Characterization untreated GLZ or Na–GLZ were determined in the aque- Fourier transform infrared (FTIR) spectra were recorded ous phase using the HPLC analysis described previously using a Shimadzu FTIR spectrometer (Shimadzu 8400S IR in the solubility studies. Partition coefficient experiments spectrophotometer, Japan) for untreated GLZ and Na– were conducted in triplicate. 50 Dissolution Technologies | NOVEMBER 2014 Formulation and Preparation of Tablets Untreated GLZ (80 mg) or an equivalent amount of Na– GLZ was mixed with lactose (50% w/w) and starch (10% w/w) to obtain a final powder weight of 200 mg for each tablet. At the concentration employed, starch attained the desired disintegration properties. Powder compression was carried out in a 7-mm die at a force of 10 kN using a manual hydraulic press. To prevent sticking of com- pressed tablets, the punch and die were first lubricated with a solution of 5% w/v magnesium stearate in 96% v/v ethanol.

Dissolution Tests Comparative dissolution experiments of untreated GLZ tablets and Na–GLZ tablets were carried out using a Cop- ley Scientific dissolution apparatus (DIS6000, Copley, UK). The tests were performed according to pharmacopoeial specifications using Apparatus 2 (paddle method). The three media employed for testing were 0.1 M HCl, pH 4.5 phosphate buffer, and pH 6.8 phosphate buffer. Paddle rotation was set at 75 rpm. Medium temperature was set at 37 ± 0.5 °C. Six tablets of each formulation were placed one in each vessel containing 900 mL of the test medium. Samples (2 mL) were withdrawn at predetermined time Figure 2. DSC thermograms of (A) GLZ and (B) Na–GLZ. points (10, 20, 30, 45, 60, and 120 min), and the volume withdrawn was taken into consideration when calculating the percentage release of GLZ or Na–GLZ in the remain- To ensure the absence of sodium hydroxide from the ing volume of test medium. Filtration of samples was obtained solid salt, it was titrated potentiometrically with performed in situ via resident probes to which polyethyl- standardized HCl solution. Accordingly, the starting pH ene filters were connected and designed to be left in the of the salt solution (150 mg/30 mL water) was 6.85, which dissolution vessel for the duration of the test. indicated absence of excess sodium hydroxide. Further- The percentage release of gliclazide from both formula- more, the percentage purity of the salt on molar basis of tions was determined using the HPLC method described Na–GLZ was 98.9%. above. The linearity of the method over the expected The IR spectra for untreated GLZ were consistent with concentration range was validated by injecting standard those reported (14). The most significant changes in the IR solutions of gliclazide in the concentration range of spectrum of GLZ compared with that of Na–GLZ (Figure 18–115 μg/mL, which covers 20–125% of the anticipated 3) were (1) the obvious shift in the sulfonamide band from 100% concentration (i.e., the concentration resulting from 1650 cm-1 in untreated GLZ to 1710 cm-1 in Na–GLZ and (2) the dissolution of an 80 mg gliclazide tablet in 900 mL of the bands in the region of 3500 cm-1 that were sharper and medium). A representative calibration equation is given fewer in number in the case of GLZ. These changes agree by: A = 23693 x - 106.7 with an average correlation coef- with the decreased ability to form intermolecular hydrogen ficient of 0.9984. bonds (involving sulfonamide oxygen and a proton) in the salt form due to loss of acidic hydrogen, while the likeli- RESULTS AND DISCUSSION hood of sulfonamide–water hydrogen bonding is increased Characterization of Na–GLZ in the salt form. Further evidence for salt formation came The dried precipitate of Na–GLZ was subjected to DSC from NMR spectra of the prepared salt and untreated GLZ. analysis, and the thermogram (Figure 2) clearly shows a The broad signal at δ = 9.9 in the spectrum of GLZ, which melting transition at 308 °C that was also confirmed by sim- corresponds to the acidic sulfonamide proton, is complete- ple measurements of the melting point of the compound. ly absent in the spectrum of Na–GLZ indicating the replace- Under the same conditions, a DSC thermogram was also ment of hydrogen by sodium. obtained for an untreated GLZ sample and shows a melting UV spectra for solutions prepared to contain the same point at 168 °C, which is consistent with the reported values mass of either GLZ or Na–GLZ were almost identical, with (27). In comparison, Na–GLZ exhibited a melting point that λmax at 233 nm. The observation that the Na–GLZ spec- is significantly higher than that of untreated GLZ, which is trum showed slightly less absorbance (93.3%) than that of consistent with the ionic nature of the salt where intermo- GLZ over the entire wavelength range is attributed to the lecular attraction forces are stronger. content of sodium in the prepared salt, which accounts Dissolution Technologies | NOVEMBER 2014 51 ity obtained at pH 4.5 within the examined values; the solubility increased at the extremely low pH of 1.2, and the maximum solubility was observed in a buffer of pH 6.8. This trend of GLZ solubility was consistent with previously published reports (28) and can be explained as GLZ is both an acid due to its sulfonamide proton with pKa of 5.8 (28, 29) and a base due to the alicyclic aliphatic amino group with pKa of 2.9 (28). Thus, within the studied pH values, the drug is expected to be in its minimum ionization state at pH 4.5. At higher pH values, the sulfonamide group starts to deprotonate, acquiring a negative charge. At lower pH values (i.e., 1.2), the alicyclic amino group would be protonated so that the molecule would possess a positive charge. In comparison, the solubility of Na–GLZ was 17 times higher than that of GLZ in a medium of pH 4.5, 30 times higher in a medium of pH 6.8, and 235 times higher in unbuffered distilled water. Therefore, salt formation re- sulted in a dramatic increase in the solubility of gliclazide, which could provide a faster dissolution rate of the drug (in distilled water, pH 4.5, and pH 6.8) and consequently a more rapid therapeutic effect. However, at a pH value of 1.2, the solubility of the salt was even slightly less than that of GLZ, which corresponds with previous observations on GLZ itself (28), that is, at the low pH value (1.2), the ionization of the weakly basic amino group seems to predominate the effect of the acidic sulfonamide group that is essentially not ionized at pH 1.2. Consequently, the molecule would be slightly more soluble as a result of the polarization imposed by Figure 3. FTIR spectra of (A) GLZ and (B) Na–GLZ. the positive charge on the amino nitrogen. The octanol–water partition coefficient expressed as log P was also determined for both GLZ and Na–GLZ. The for almost the same percentage (6.64%) of sodium in the log P values of 2.04 and 0.68 were obtained for GLZ and molar mass of Na–GLZ. Na–GLZ, respectively (RSD less than 3.1%). These results Using a previously published stability indicating HPLC agree with the previously published data for the parti- method (26), both GLZ and Na–GLZ eluted at the same tion coefficient of gliclazide (7, 30). Accordingly, the salt retention time with no significant additional peaks. Based form is approximately 20 times more hydrophilic than the on a calibration curve in which standard solutions were untreated form. Nevertheless, the values of log P for Na– prepared from standard GLZ, the purity of prepared GLZ are still within the recommended optimum range of Na–GLZ was estimated to be 99.1% on a molar basis. The typical drugs (31). purity calculated on a mass basis for GLZ salt was 92.1%, which again accounts for the percentage of sodium and Dissolution Properties of Na–GLZ the estimated water content (0.14% determined by Karl Tablets of each of GLZ and Na–GLZ were prepared to Fisher method) in Na–GLZ. Thus the identity and purity contain the equivalent of 80 mg GLZ. Content uniformity of the prepared material was confirmed to be the sodium testing was performed to ensure homogeneity of the tab- salt of GLZ with a purity of 99.1%. let mix and uniform content of the desired dose utilizing the HPLC method described in the Experimental section. Solubility and Partition Coefficient The assayed percentage per label for GLZ and Na–GLZ The solubility of GLZ as well as prepared Na–GLZ was tablets where in both cases within ±5% and with RSD val- determined in distilled water and in media of three ues less than 1.9%. Dissolution profiles were obtained for relevant pH values (1.2, 4.5, and 6.8), as these pH values GLZ and Na–GLZ in 0.1 M HCl (pH 1.2), pH 4.5 phosphate are generally recommended for testing the dissolution buffer, and pH 6.8 phosphate buffer (4). A summary of the performance of solid oral dosage forms (4). A summary of dissolution profiles obtained is presented in Figure 4. In the obtained solubility data is shown in Table 1. all media, the dissolution rate of Na–GLZ was higher than According to the data presented in Table 1, the solubil- that of GLZ with the lowest observed difference in dis- ity of GLZ was pH dependent with a minimum solubil- solution rate observed at pH 1.2. The highest difference in 52 Dissolution Technologies | NOVEMBER 2014 Table 1. Solubility Data for GLZ and Na–GLZ at 37 ± 0.1 °C

Solubility μg/mL (RSD) Distilled water 0.1 M HCl pH 1.2 Phosphate buffer pH 4.5 Phosphate buffer pH 6.8 GLZ 52.6 (4.6) 124.2 (2.1) 40.4 (3.8) 182.4 (5.3) Na–GLZ 12369.7 (0.25) 94.6 (15.7) 714 (4.2) 5421.7 (8.3) n = at least three

pH 1.2 is almost 4 pH units less than the pKa of gliclazide, the conversion of the salt to the undissociated acid form is quite likely, which explains the observed effect. Never- theless, that should not preclude making use of the high solubility and dissolution rate demonstrated by the salt at slightly acidic and near neutral pH values, since this limita- tion could simply be overcomed by developing an enteric coated tablet formulation of the salt, which escapes the highly acidic medium of the stomach. It is noteworthy that in each medium, the percentage release of Na–GLZ reached its maximum within the first 15–20 min, while for GLZ it continued to increase gradu- ally up to the end of dissolution test (120 min). This rapid dissolution observed for Na–GLZ together with the higher overall percentage release is particularly important for a drug like gliclazide (antidiabetic) where the action is usually required to start rapidly. Clinically used formulations Figure 4. Dissolution profiles of gliclazide (dashed lines) and sodium gli- of GLZ tablets typically require 2–8 h to reach maximum clazide (solid lines) at (■) pH 1.2, (●) pH 4.5, and (▲) pH 6.8. The RSD for all data points were generally less than 8%. plasma concentration, which could be considered a shortcoming (8). This latency in achieving maximum concentration is a result of the low dissolution rate of the dissolution rate was observed at pH 6.8 where it reached drug, where a faster dissolving soft gelatin formulation approximately 60% at 30 min. In the buffer medium of pH was shown to achieve higher Cmax within a 36% shorter 4.5, the percentage dissolved of the salt was 30% higher time (20). Previous reports (20, 28, 32) demonstrate that than that of GLZ within the first 20 min. dissolution of gliclazide, particularly at lower pH values, Nevertheless, the dissolution profile of Na–GLZ at pH 4.5 is an important determinant of its rate of absorption and show a plateau at only 40% of drug dissolved, which was consequently its onset of action with reasonable correla- not expected in light of the solubility data of the salt at tion between in vitro dissolution and in vivo bioavail- pH 4.5 (i.e., 714 μg/mL), whereas the expected 100% dis- ability. Thus, the prepared Na–GLZ might offer a potential solved was 88.9 μg/mL. In addition to the possibility of the improvement in the onset of action of gliclazide and a salt being converted (to some extent) to the undissociated decrease in inter-individual variability of its absorption, acid form, other reasons might contribute to the observed which might lead to better clinical outcomes. Although effect. Such reasons may include the mechanical shak- several approaches have been described to improve the ing of the solubility vial versus the rotation speed of the solubility and dissolution of gliclazide, salt formation of- dissolution system paddle, but the most important reason fers the advantages of simplicity, low cost, and possibility was perhaps the fact that the dissolution test was per- of large-scale production. formed on formulated tablets, whereas the solubility was performed on a drug powder. One possible factor, in this CONCLUSION regard, may be the lubricant magnesium stearate where The sodium salt of gliclazide was prepared by an easy its use in tablets is well known to affect disintegration and and potentially large-scale method. The prepared salt dissolution properties. However, the extent of dissolution was fully characterized using DSC, HPLC, NMR, UV, and IR for the prepared sodium salt was still at least six times methods. 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